U.S. Pat. No. 7,056,898 (the '898 patent) discloses and claims certain hypersulfated disaccharides and methods of using same to treat certain inflammatory disorders. This patent specifically describes the use of the claimed compounds to treat pulmonary inflammations including asthma and asthma-related pathologies, such as allergic reactions or an inflammatory disease or condition. The compounds disclosed therein are described as being capable of preventing, reversing and/or alleviating the symptoms of asthma and asthma-related pathologies, particularly the late phase response in asthma patients following antigen stimulation. The examples and figures shown therein specifically relate to intravenous and inhalation means of administration of the recited disaccharides. In the '898 patent there is a general disclosure of the oral administration of a hypersulfated disaccharide designated as 811-25-1 at a dose of 0.5 mgs/kg to sheep, but no specific data is shown. There is also no disclosure therein of any specific oral formulation nor any specific disclosure of any data related to administration of a specific oral formulation. There is a need for an improved pulmonary or anti-inflammatory medication that can be delivered in small dosages to patients in need of treatment thereof on a convenient basis and which does not have the side effects associated with, for example, chronic administration of steroids or leukotriene receptor antagonists such as montelukast sodium.
The inventor has met this unmet need and has surprisingly found that certain formulations comprising the hypersulfated disaccharides recited herein and a delivery agent selected from the group consisting of a pharmaceutically acceptable natural or synthetic polymer as well as other vehicles that heretofore have been utilized to improve delivery of large compounds (e.g., those compounds having molecular weights of greater than 4,500 daltons as average molecular weight) have enhanced absorption/bioavailability/efficacy relative to the same compounds delivered without the claimed additives. While the literature has disclosed that certain carbomers enhance the intestinal absorption of Low Molecular Weight Heparins (LMWH) having, molecular weights of approximately 4500 daltons, there has been no teaching or suggestion of the use of such materials to enhance the absorption of low molecular weight disaccharides. In fact, as reported in Thanou et al., Pharmaceutical Research, 18 (11) 2001, such carbomers were added because of the large size of the LMWHs which, it was thought, would have difficulty permeating across the intestinal epithelium via transcellular or paracellular routes (via passage through the tight junction) albeit with less difficulty than fractions having a molecular weight of 12,000 daltons. The same would not apply to low molecular disaccharides which are, when compared to LMWHs, small molecules which can more readily permeate across the intestinal epithelium. The present inventors have unexpectedly found that low molecular weight disaccharides, in particular, low molecular weight hypersulfated disaccharides (e.g., of about 1,000 daltons), have surprisingly better efficacy when combined with a polymeric material having at least one of the chemical and/or physical properties of, for example, Carbopol 934 P and/or other carbomers. Such polymers have ionic groups such as a carboxylic acid side chain and/or hydrophilic moieties which facilitate the delivery of the hypersulfated disaccharides of the invention.